There remains a need for improved therapeutics useful in the treatment of cancer. The Warburg effect in cancer cells consists of an increase in aerobic glycolysis and enhanced lactate production, which generates more ATPs more quickly than in normal cells that overwhelmingly rely on oxidative phosphorylation. In addition, tumor tissue traps more glucose than normal tissue does, as cancer cells use elevated amounts of glucose as a carbon source for anabolic biosynthesis of macromolecules. These include nucleotides, amino acids and fatty acids, to produce RNA/DNA, proteins and lipids, respectively, which are used for cell proliferation and to fulfill the request of the rapidly growing tumors. Interestingly, leukemia cells are also highly glycolytic, despite that such cells reside within the bloodstream at higher oxygen tensions than cells in most normal tissues, as well as tumor cells that commonly reside in hypoxia. This suggests that tumor hypoxia may not be a major contributor to select for cells dependent on anaerobic metabolism.
During glycolysis, glycolytic intermediates including glucose-6-phosphate (G6P) can be diverted into the pentose phosphate pathway (PPP), which contributes to macromolecular biosynthesis by producing reducing potential in the form of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and/or ribose-5-phosphate (R5P), the building blocks for nucleotide synthesis. NADPH is the most crucial metabolite produced by the PPP because NADPH not only fuels macromolecular biosynthesis such as lipogenesis, but it also functions as a crucial antioxidant, quenching the reactive oxygen species (ROS) produced during rapid proliferation of cancer cells.
Glycolysis and glutaminolysis supply the carbon input required for the TCA cycle to function as a biosynthetic ‘hub’ and permits the production of other macromolecules including amino acids and fatty acids. Thus, cancer cells appear to coordinate glycolysis and anabolism to provide an overall metabolic advantage to cancer cell proliferation and disease development.
Engel et al., report that a phosphoglycerate mutase-derived polypeptide inhibits glycolytic flux and induces cell growth arrest in tumor cell lines. J Biol Chem, 2004, 279, 35803-35812.
Evans et al., report the mechanistic and structural requirements for active site labeling of phosphoglycerate mutase by spiroepoxides. See Mol. BioSyst., 2007, 3, 495-506.
PCT Patent Application PCT/US2009/000257, published as WO 2010/082912 A1 discloses certain disulfonamide derivatives. The disclosure also discloses methods for treating tumors and cancer.